tbuckley/cabot-search huggingface dataset:
Abstract 6117: Clinical and molecular correlates of immune marker profiling and PD-L1 expression in non-small cell lung cancer
Authors: Yunfei Shi, Youming Lei, Yinqiang Liu, Jin Duan, Wei Zhao, Fujun Zhang, Guoli Lv, Qian Wu, Mengmeng Wu, Jiani C. Yin, Yang Shao
Journal: Cancer Research (2022)

Abstract Background: Understanding the genomic landscape and tumor immune microenvironment of non-small cell lung cancer (NSCLC) may provide critical insight into the biology of tumor immune response and novel strategies for overcoming immunotherapy resistance. The association of clinical and genomic features with tumor immune microenvironment in NSCLC patients remains unclear. Methods: In this retrospective cohort study, we profiled PD-L1 and immune cell marker expressions and performed targeted next-generation sequencing (Geneseeq Technology Inc., Nanjing) of baseline tissue samples from 100 NSCLC patients. The levels of CD8+, CD68+ and HLA-DR+ immune cells were assessed by multiplexed immunohistochemistry (mIHC) assay. Immune microenvironment markers and PD-L1 expression was analyzed for associations with clinical features and mutations at both the single gene and pathway levels. Results: Mutations in TP53, SETD2, RET and the p53 signaling pathway were significantly associated with high PD-L1 high expression (P&amp;lt;0.001; P=0.002; P=0.04; P=0.001, respectively). Patients with high PD-L1 expression showed a trend towards higher stromal CD8+ lymphocytes (P=0.1), Alterations in T cell and B cell pathways were also associated with increased stromal CD8+ T cells (P=0.03 and P=0.08, respectively). The infiltration of intratumoral CD68(+)HLA-DR(+) M1-like macrophages positively correlated with high PD-L1 high expression (P=0.07), Hippo pathway alterations (P=0.06). By contrast, the levels of intratumoral M1-like macrophages negatively correlated with alterations in the NRF2/KEAP1 pathway (P=0.005), which might account for the poor immunotherapy outcome in this subset of patients. Conclusions: Our study demonstrates the complex relationship between gene mutations and aberrations in signaling pathways with the immune microenvironment in NSCLC. Specific molecular features are associated with unique immune profiles and may impact the response to immune checkpoint inhibitors. Citation Format: Yunfei Shi, Youming Lei, Yinqiang Liu, Jin Duan, Wei Zhao, Fujun Zhang, Guoli Lv, Qian Wu, Mengmeng Wu, Jiani C. Yin, Yang Shao. Clinical and molecular correlates of immune marker profiling and PD-L1 expression in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6117.
Abstract 2067: NL-201, a de novo engineered IL2/IL15 mimic, synergizes with radiation to generate potent antitumor immunity
Authors: Xuefeng Li, Kristin Huntoon, Yifan Wang, Carl Walkey, Betty Y. Kim, Wen Jiang
Journal: Cancer Research (2022)

Abstract There is a growing interest in combining radiotherapy (RT), a standard of care treatment for many cancer types, with immunotherapeutic agents to improve efficacy. One such approach is RT in combination with high-dose recombinant interleukin 2 (IL-2), which elicits anti-tumor immune responses by stimulating T-cell and NK cell populations. Although effective for some patients, the overall clinical benefit of high-dose recombinant IL-2 is limited by toxicity and the expansion of regulatory T cells (Tregs) through signaling events mediated by IL2RΑ (CD25). In this study, we examined RT in combination with NL-201, a highly potent and stable CD25-independent IL-2 and IL-15 receptor agonist with enhanced affinity for IL2RΒ and IL2RΓ. Single-agent NL-201 was well-tolerated in mice, yielded tumoricidal activity, expanded peripheral T cells, and enhanced the infiltration of effector T cells and dendritic cells (DCs) into murine breast cancers. In combination with RT, NL-201 enhanced activation of the cytosolic DNA sensor cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, resulting in increased type I interferon (IFN) production in DCs and, consequently, greater tumor infiltration by T cells and more efficient priming of antigen-specific T cells by professional antigen-presenting cells (APCs). The immune stimulatory mechanisms triggered by the NL-201 and RT combination resulted in superior tumor growth inhibition and survival benefit in both localized and metastatic murine breast cancers, including those spread to the central nervous system. Genetic knockout of STING in host cells abrogated the activity of the NL-201 and RT combination, thus confirming the crucial role of innate immune sensors in the combination treatment’s antitumor responses. Additionally, when combined with PD-1 antibodies, NL-201 significantly improved growth inhibition of metastatic breast cancers that were previously resistant to checkpoint blockade. We demonstrated that the CD25-independent IL-2 and IL-15 receptor agonist, NL-201, in combination with RT is well-tolerated and elicits robust anti-tumor activity through both innate and adaptive responses, including in checkpoint resistant tumors and brain metastases. Furthermore, we identify a unique mechanism in which NL-201 synergizes with RT, likely via the direct activation of STING in DCs. Taken together, the results provided herein support further preclinical and clinical investigation of this novel combination regimen in both localized and metastatic settings. Citation Format: Xuefeng Li, Kristin Huntoon, Yifan Wang, Carl Walkey, Betty Y. Kim, Wen Jiang. NL-201, a de novo engineered IL2/IL15 mimic, synergizes with radiation to generate potent antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2067.
Abstract 163: Regulation of periostin by DDR2 in cancer-associated fibroblasts controls tumor invasion and metastasis in ovarian cancer
Authors: Favour A. Akinjiyan, Ritu M. Dave, Katherine C. Fuh
Journal: Cancer Research (2022)

Abstract Ovarian cancer has the highest mortality of all gynecological malignancies. As such, there is a need to decipher molecular mechanisms that underlie tumor metastasis in ovarian cancer. Increased expression of receptor tyrosine kinase, DDR2, has been associated with worse patient survival. Identifying downstream targets of DDR2may allow specific modulation of ovarian cancer metastatic pathways with few off-target effects. Additionally, stromal cells play a critical role in metastasis. The crosstalk between tumor and stromal cells cans hift the balance between tumor progression or inhibition. We identified periostin to be highly expressed by fibroblasts expressing DDR2compared to fibroblasts without DDR2(Fold change=2.0, P=0.03).We show that DDR2regulates periostin in ovarian cancer associated fibroblast (CAFs). DDR2and periostin expression in the CAFs leads to512% increase in mesothelial cell clearance ratio(P=0.0004) and matrigel invasion(612vs 193invading cells/hpf, P&amp;lt;0.0001). Mice injected withCAFs expressing periostin as well as ovarian cancer tumor cells have 72% increased tumor burden compared to mice with CAFs that do not express periostin (P=0.006). High periostin expression in CAFs leads to decreased T-cell proliferation and cytotoxicity. We validate periostin as a marker for patient outcome in ovarian cancer patients. Patients with high periostin expression have worse overall survival thant hose with low periostin expression. Mapping regulatory networks involved in tumor initiation and progression is important for identification of novel therapeutic targets. Citation Format: Favour A. Akinjiyan, Ritu M. Dave, Katherine C. Fuh. Regulation of periostin by DDR2 in cancer-associated fibroblasts controls tumor invasion and metastasis in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 163.
Abstract 1399: Discovery and development of PARP inhibitor senaparib
Authors: Sui Xiong Cai, Ning Ma, Xiaozhu Wang, Yangzhen Jiang, Mingchuan Guo, Chih-Yi Hsieh, Ye Edward Tian
Journal: Cancer Research (2022)

Abstract Poly (ADP-ribose) polymerase (PARP) is a key enzyme for DNA repair. PARP inhibitors have been shown to be effective against cancers with DNA repair defects, such as with BRCA1 or BRCA2 mutations. Several PARP inhibitors, including olaparib, rucaparib, niraparib, talazoparib, fluzoparib and pamiparib have been approved for the treatment of several types of cancer. In this presentation, we will report our discovery and development of senaparib (IMP4297) as a potent PARP inhibitor. We will present studies led to the identification of senaparib as a clinical candidate, as well as IND enabling in vitro and in vivo characterization of senaparib. Preclinical data indicated that senaparib had a wide therapeutic window (single agent effective dose of 2.5-21 mg/kg QD, in a BRCA1 mutated MDA-MB-436 human breast cancer xenograft model), which was confirmed in clinical studies (effective dose of 20-120 mg QD, and no DLT was found up to 150 mg QD). Senaparib is currently in several phase I/II, phase II and phase III clinical studies for the treatment of multiple tumor types either as single agent or in combination with temozolomide (TMZ). The most advanced study of senaparib is a phase III study as maintenance therapy in platinum-sensitive advanced ovarian cancer patients following first-line chemotherapy (ClinicalTrials.gov Identifier: NCT04169997). Citation Format: Sui Xiong Cai, Ning Ma, Xiaozhu Wang, Yangzhen Jiang, Mingchuan Guo, Chih-Yi Hsieh, Ye Edward Tian. Discovery and development of PARP inhibitor senaparib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1399.
Abstract 5665: LILRB2 mediates the immune escape of breast tumor cells by degrading HLA-A
Authors: Hui Zhao, zhiyuan jiang, zhiyu wang, yujie chang, shunyi ruan
Journal: Cancer Research (2022)

Abstract Breast cancer has now risen to the number one cancer in the world, posing a great threat to human health. LILRB2 (leukocyte immunoglobulinlike receptor B2) is an important immunosuppressive receptor protein, which is mainly expressed in myeloid cells, such as macrophages and dendritic cells. At present, we have found clinically that patients with breast cancer bone and bone marrow metastasis have higher expression of LILRB2. In our research, we used Western blotting, real-time fluorescent quantitative Polymerase Chain Reaction (RT-PCR), flow cytometry, and other experimental methods to explore the expression and function of LILRB2 in breast cancer cells. In our research, we found that LILRB2does increase expression in breast cancer cells, therefore, we want to explore the role of LILRB2 in breast cancer cells. we find that LILRB2 will accelerate the proliferation of tumor cells and increase their migration ability. We tested the related signal pathways and found that LILRB2 can promote the enhancement of the NF-Kb signal pathway. Further, we have done related LILRB2 correlation analysis and found that LILRB2 can reduce human leukocyte antigen-A (HLA-A) Expression. Next, we tested the changes in the level of major histocompatibility complex (MHC-1) related mRNA and found that its mRNA expression increased, which was inconsistent with the decrease in its protein level we observed. Therefore, we used the proteasome inhibitor MG132 for treatment, and the results showed after adding MG132, the decrease in HLA-A expression caused by overexpression of LILRB2 was restored. Next, we knocked down the breast cancer cell line of membrane-associated ring finger (MARCH9). After we knocked down MARCH9, transfection of LILRB2 did not increase the ubiquitination of HLA-A. Therefore we show that LILRB2 can mediate the post-translational modification of HLA-A via MARCH9, which in turn mediates the degradation ofHLA-A. In conclusion, our research shows that LILRB2 maybe a candidate of clinical target for the treatment of breast cancer, preventing possible bone and bone marrow metastasis from breast cancer. Citation Format: Hui Zhao, zhiyuan jiang, zhiyu wang, yujie chang, shunyi ruan. LILRB2 mediates the immune escape of breast tumor cells by degrading HLA-A [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5665.
Abstract 5316: Risk of cognitive impairment associated with androgen deprivation therapy in prostate cancer
Authors: Shiv Verma, Eswar Shankar, Viabhav Singh, Sanjay Gupta
Journal: Cancer Research (2022)

Abstract Androgen deprivation therapy (ADT) is a commonly used clinical treatment for non-metastatic and metastatic hormone-sensitive prostate cancer. Long-term ADT treatment results in adverse side-effects in patients including depression, frailty, cognitive impairment and dementia. Studies have reported increased levels of pro-inflammatory cytokines and inflammatory markers in older cancer patients, however, the relationship between inflammatory biomarkers and the severity of cognition in prostate cancer patients under ADT has not been investigated. We sought to identify peripheral biomarkers that could provide links between the mental changes and major pathological mechanisms responsible for the development of cognition in these patients. For these studies, gene expression data (GSE69223) of 30 matched malignant and non-malignant prostate tissue samples from 15 prostate cancer patients receiving neoadjuvant antiandrogen therapy before prostatectomy, were compared in parallel with postmortem brain tissue samples of Parkinson's and Alzheimer patients as additional neurological diagnosis. IPA analysis was performed in the context of known biological response and regulatory networks. Fisher’s exact test for each network was converted to a score of −log10 (p-value). Further validation was performed in BT142-neural cells and M059K-glial cells by qRT-PCR with and without antiandrogen (enzalutamide) treatment. A total of 1952 DEGs were identified in postmortem brain tissue specimens, and 101 DEGs were identified in prostate cancer patients receiving ADT before surgery. IPA analysis revealed 33 commonly expressed genes with changes in cytokine-cytokine signaling network overlapped in both patient cohorts. Pathway analysis showed that IL17 signaling pathway, regulation of cytokine production and changes in T-cell subsets by IL-17A and IL-17F were overrepresented. Furthermore, lipopolysaccharide, tumor necrosis factor and toll-like receptors were identified as upstream transcriptional regulators of these signaling pathways. Gene expression of pro-inflammatory cytokines viz. LIFR, IL1RN, IL6, IL10 and LIF were increased in both neural and glial cells treated with enzalutamide, compared to non-enzalutamide treated cells. Our results suggest that changes in cytokine signaling under the influence of ADT in prostate cancer patients may linked with cognitive impairment presenting new areas for diagnostic and therapeutic development in combating brain deficits. Citation Format: Shiv Verma, Eswar Shankar, Viabhav Singh, Sanjay Gupta. Risk of cognitive impairment associated with androgen deprivation therapy in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5316.
Abstract 2404: Role of TPD52L2 in cell migration and triple negative breast cancer progression
Authors: Seyedamirabbas Parizadeh, Stephan Geley, Veronika Reiterer-Farhan, Hesso Farhan
Journal: Cancer Research (2022)

Abstract The Golgi apparatus plays an important role in cell migration and the establishment of epithelial polarity. A dispersed (or fragmented) Golgi ribbon is often seen in stressed cells and in various pathologies, including neurodegeneration or cancer, but whether and how a fragmented Golgi apparatus affect cellular function is poorly defined. Previously our lab has performed and analyzed published RNAi screens to identify genes required to maintain the Golgi ribbon. These candidate genes were filtered for altered expression patterns in breast cancer patients and for their association with survival data. The selected genes reevaluated by RNAi in BT549 breast cancer cells to assess the effect on Golgi fragmentation. One of the most effective hits was TPD52L2, a poorly characterised gene that encodes a membrane-associated protein that is overexpressed in various types of cancer. The aim of this project is to investigate the role of TPD52L2 in cell migration and cell invasion in breast cancer in order to understand the role of Golgi fragmentation in tumorigenesis. In random cell migration assays in dense and sparse seeding conditions, TPD52L2 depleted cells showed an altered actin cytoskeleton and were found to migrate faster in dense seeding without any change in directional persistence. These findings suggest that TPD52L2 not only is required to maintain an intact Golgi structure but also plays an important role in cellular motility and potentially metastasis. Citation Format: Seyedamirabbas Parizadeh, Stephan Geley, Veronika Reiterer-Farhan, Hesso Farhan. Role of TPD52L2 in cell migration and triple negative breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2404.
Abstract 1531: CD146 couples and sequesters regulatory kinases to control breast cancer cell state plasticity
Authors: Ozlen Balcioglu, Brooke L. Gates, David W. Freeman, Berhane M. Hagos, Benjamin T. Spike
Journal: Cancer Research (2022)

Abstract CD146 (Mcam; Muc18; s-endo; and gicerin) is an integral membrane glycoprotein originally identified in a human malignant melanoma, but mis-expressed in a wider variety of malignancies including breast cancer, where it has been implicated in controlling tumor growth and dissemination. The mechanisms by which CD146 conveys extracellular cues into malignant cellular outputs is not well understood, but its high-level expression in early development and normal mouse mammary stem cells, as well as expression in highly plastic adult pericytes (formerly known as mesenchymal stem cells) suggested to us that it may control cell state plasticity. We tested the role of CD146 in a plastic, stem cell-like mouse mammary tumor cell line derived from the MMTV-PyMT mouse (PY230). We identified domains in the CD146 cytoplasmic tail essential for controlling substrate utilization by upstream kinases in Akt, Mapk, Stat3, and integrin-related signaling pathways that alter cell state plasticity and tumorigenicity. This work suggests that MCAM plays a key role in controlling lineage plasticity in normal and neoplastic mammary cells with relevance for understanding tumor cell plasticity, progression and evasion of targeted cancer therapies. Citation Format: Ozlen Balcioglu, Brooke L. Gates, David W. Freeman, Berhane M. Hagos, Benjamin T. Spike. CD146 couples and sequesters regulatory kinases to control breast cancer cell state plasticity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1531.
Abstract 2798: A multi-biomarker panel of nuclear transport proteins with potential as novel secreted cancer biomarkers
Authors: Pauline van der Watt, Michael Okpara, Andrew Wishart, Iqbal Parker, Nelson Soares, Jonathan Blackburn, Virna D. Leaner
Journal: Cancer Research (2022)

Abstract Members of the nuclear transport protein family have been identified to have increased expression in many cancer types, with some being investigated as anticancer therapeutic targets. Recently, individual nuclear transport proteins have been reported to be secreted by cancer cells and found in the serum of cancer patients. In this study we investigated a multi-marker panel of nuclear transport proteins for their potential as diagnostic markers for cancer using cervical and oesophageal cancer as disease models. Mass spectrometry identified ten nuclear transport proteins in the secretome and exosomes of cultured cancer cells which was confirmed by western blot analysis showing increased secreted levels in cancer cells compared to normal. The presence of multiple nuclear transport proteins was confirmed in patient serum using ELISA assays which revealed significantly increased levels of KPNβ1, CRM1, CAS, IPO5 and TNPO1 in cervical and oesophageal cancer patient serum compared to non-cancer controls. Significantly elevated KPNα2 and RAN levels were also identified in oesophageal cancer serum samples. Logistics regression analyses revealed IPO5 and TNPO1 to be the best performing individual candidate biomarkers in discriminating between cancer cases and controls. The combination of KPNβ1, CRM1, KPNα2, CAS, RAN, IPO5 and TNPO1 as a multi-marker panel of biomarkers had the highest diagnostic capacity with an area under the curve (AUC) of 0.944 and 0.963, for cervical cancer and oesophageal cancer, and sensitivity of 92.5% at 86.8% specificity and 95.3% sensitivity at 87.5% specificity, respectively. These results suggest that nuclear transport proteins have potential as diagnostic biomarkers for cervical and oesophageal cancers, with a multi-panel protein combination being the best predictor. Citation Format: Pauline van der Watt, Michael Okpara, Andrew Wishart, Iqbal Parker, Nelson Soares, Jonathan Blackburn, Virna D. Leaner. A multi-biomarker panel of nuclear transport proteins with potential as novel secreted cancer biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2798.
Abstract CT166: Injection site reactions correlate to delayed type hypersensitivity tests and suggest that GP2 reverses immune suppression of trastuzumab-treated HER2 positive patients in a phase IIb study evaluating HER2/neu peptide GP2 (GLSI-100) vs. GM-CSF after adjuvant trastuzumab in HER2 positive women with breast cancer
Authors: Snehal S. Patel, David B. McWilliams, Mira S. Patel, Jaye Thompson, F. Joseph Daugherty
Journal: Cancer Research (2022)

Abstract The authors did not submit an updated abstract. The original abstract should be considered final. Citation Format: Snehal S. Patel, David B. McWilliams, Mira S. Patel, Jaye Thompson, F. Joseph Daugherty. Injection site reactions correlate to delayed type hypersensitivity tests and suggest that GP2 reverses immune suppression of trastuzumab-treated HER2 positive patients in a phase IIb study evaluating HER2/neu peptide GP2 (GLSI-100) vs. GM-CSF after adjuvant trastuzumab in HER2 positive women with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT166.